The proposed research represents a multidisciplinary approach to problems in allografts and tumor immunity as they relate to specific adoptive immunotherapy for the treatment of advanced cancer. The main focus of the research will be to investigate factors influencing successful sensitization of donor immunocompetent cells against antigens present on the surface of malignant cells. The studies will be conducted in AKR mice bearing spontaneous T cell leukemia. In an attempt to minimize the complication of graft-versus-host disease, mice that are allogeneic, but are compatible with AKR at the major histocompatibility complex, will be used as donors of immunocompetent cells for adoptive immunotherapy of AKR leukemia. Allosensitization will be used in an effort to generate effector cells in the donors mice which will have reactivity against the leukemia of AKR mice but not their normal tissues. Both individual and pool allosensitization will be investigated. A primary objective will be to investigate the nature of the antigens or cross-reacting antigens on AKR leukemia cells which serve as targets for adoptive immunotherapy following allosensitization; "alien" H-2 antigens, minor histocompatibility antigens, murine leukemia virus antigens, and fetal antigens will be studied. The nature of the effector cell after allosensitization and the antitumor specificity (or lack of specificity) will be investigated. The ability of allosensitization to induce resistance to transplants of AKR leukemia cells in susceptible strains of mice and to prevent the development of spontaneous leukemia in AKR mice will be tested. Effector cells from allosensitized donors will be used in combination with chemoradiotherapy for adoptive immunotherapy of AKR mice bearing advanced spontaneous leukemia. We are hopeful that insights gained in these studies of principles regulating the generation of sensitized cytotoxic effector cells in histocompatible donors will help elucidate successful approaches to the immunotherapy of malignancy in man.